Description

Cytokine production by Th17 cells in CF (Mouse Model)

Cystic Fibrosis (CF) is a potentially lethal genetic disease that typically results in
the development of bronchial inflammation, bronchiectasis, the progressive loss of lung
function and, ultimately, death [1].

CF is caused by genetic defects in Cystic Fibrosis Transmembrane Conductance Regulator
( CFTR ) gene which encodes a chloride channel regulating chloride transport in
the lung. CFTR mutations are associated with severe lung disease are generally
found along with little to no CFTR protein expression in the membranes of airway
epithelial cells [2]. The most common CF-causing mutation is the homozygous
deletion of a phenylalanine at amino acid position 508 (deltaF508), which accounts for
nearly 70% of defective alleles and causes nearly 90% of disease cases [2],
[1].

In the absence of normal CFTR activity, CF airways get colonized by several
bacterial species, which results in chronic stimulation of the proinflammatory signaling.
Pseudomonas aeruginosa is the predominant pathogen of CF chronic lung infection
[3].

The deltaF508 mutation results in misfolding and ubiquitynation which target the
protein for degradation. This leads to decreased amounts and poor functioning of
CFTR in the cell membrane resulting in inadequate chloride transport. Reduced
secretion of chloride and fluid hydration, as well as excessive secretion of mucins,
produce a biological matrix that facilitates growth of P. aeruginosa in biofilm.
In the absence of functional CFTR, the height of the airway surface liquid is
significantly reduced, resulting in defective volume of ciliary movement and reduced
mucociliary clearance. This defect in mucociliary clearance results in mucus stasis and
impaired antigen clearance and potentates bacterial infection [1].

Epithelial response to bacterial ligands is mediated by Toll-like receptors (TLRs)
resulting in the Nuclear Factor kappa-B (NF-kB ) activation that ultimately
induces transcription of proinflammatory cytokines, including Interleukins IL-6
and IL-8[3]. These interleukins are also produced by antigen
presenting cells (presumably by lung macrophages and dendritic cells) in response to
bacteria. Bacterial lipopolysaccharides (LPS) in the presence of the LPS binding
protein ( LBP ) are recognized by TLR4/ MD-2/ CD14 complex
followed by NF-kB activation. Production of Interleukin IL-23 (which is
composed of two subunits, alpha ( IL23A ) and beta ( IL-12 beta chain )) by
lung macrophages and dendritic cells in response to mucoid P. aeruginosa is
critical for the induction of Interleukin IL-17 and the subsequent T-cell
differentiation and neutrophilic inflammation [4], [5],
[1].

Despite the critical function of TGF-beta 1 in the differentiation of mouse
Th17 cells, several studies indicate that this cytokine is not needed for IL-17
production in human T cells; in fact, TGF-beta 1 inhibits IL-17 production
[18], [19], [11].

IL-17 is a key cytokine in CF lung that regulates granulopoiesis and neutrophil
migration. IL-17 signals through the Interleukin 17 Receptor A ( IL-17
receptor ) that can associate with Interleukin 17 Receptor C ( IL-17RC ) to
form a multimeric receptor complex [28]. IL-17RC binds both
IL-17F and IL-17[29].